1. Field of the Invention
The present invention relates generally to the treatment of Acquired Immune Deficiency Syndrome (AIDS) and other diseases or conditions where an individual's immune system is suppressed. More particularly, the present invention relates to pharmaceutical preparations which are useful in treating AIDS and other immune system disorders where the preparations include active ingredients that are derived from mistletoe.
2. Description of the Related Art
AIDS is associated with a highly infectious retrovirus called Human Immunodeficiency Virus (HIV). This virus multiplies in human lymphocytes and macrophages and with the help of a viral reverse transcriptase in incorporated into the cellular genome (as pro-viral DNA). In the acute infectious stage, the virus kills most of the infected lymphocytes, especially T4 lymphocytes. T4 lymphocytes play a central role in host immune response. T4 cells, on stimulus from a foreign antigen in presence of interleukin-1 (IL-1), undergo a series of biochemical changes which activate expression of a number of genes including those for interleukin-2 (IL-2), IL-2 receptors and gamma interferon. Substances secreted by `activated` T4 cells stimulate maturation of B cells (plasma cells) which secrete antibodies (humoral immune response) and help in maturation of (cytotoxic) T8 cells which eliminate (pathogen) infected cells, including cancer (cellular immune response). T4 cells also suppress activation of T8 cells once the infection is under control. IL-2 secreted by T4 cells binds with IL-2 receptors to stimulate division of these cells to approximately 1000 memory clones with antigen specific memory. Thus, T4 cells play a central role in host immune response.
T4 cells infected with HIV carry pro-viral DNA in their genome. Stimulation of infected T4 cells results in expression of its genes including those for HIV. The synthesis of viral RNA and proteins in the infected cells results in production of virus particles. The virus particles, as they burst out of the infected T4 cells, also destroy the host lymphocytes and restrict the production of memory clones. This depletion of T4 cells in HIV infected patients leaves them without the ability to fight even minimal infections. Thus, AIDS patients contract terminal opportunistic diseases like pneumonia, caused by a generally harmless protozoan, Pneumocystis carinii, or a cancer called Kaposi's sarcoma, a tumor of blood vessel tissue, in skin or internal organs.
Numerous treatment protocols have been developed for treating AIDS. Immunotherapy is one form of treatment which has been investigated extensively. The two exemplary types of immunotherapy used for treating AIDS are: (a) monoclonal antibodies and (b) intravenous immunoglobulin (IVIG). Monoclonal antibodies are generally murine proteins that must be "humanized" with genetic engineering to minimize the human anti-murine antibody (HAMA) response. An advantage of IVIG over monoclonal antibodies is that the HAMA response is minimal since IVIG are human proteins. In addition, IVIG is readily available from blood bank plasma. However, IVIG has usually been administered only after a patient develops AIDS in an attempt to limit infection by opportunistic viruses other than HIV.
IVIG is FDA-approved and is presently commercially available for treatment of viral and other diseases in either intravenous or intramuscular formulations. Different forms of IVIG can be generated by screening blood bank plasma for donors that have a particularly high tiler of antibody directed against a specific virus. Therefore, pooling the plasma from these viral-exposed donors provides a form of IVIG that contains high titers of antibodies targeting a specific virus, such as HIV. The use of HIV sero-positive plasma in the generation of HIV immune globulin (HIVIG) has been described and is presently in clinical trials for the treatment of AIDS. Similarly, other forms of viral specific human immune globulin are presently being studied for the treatment of other viral diseases.
The above forms of immunotherapy (e.g., monoclonal antibodies, IVIG, HIVIG) for the treatment of AIDS is limited by the poor cellular uptake of the monoclonal antibody or immune globulin. This is because the virus replicates in the intracellular space of cells; therefore, effective neutralization of the virus requires "intracellular immunization." Owing to the poor transport of monoclonal antibodies or immune globulins into cells, these agents generally allow only for intravascular or extracellular immunization in vivo in living subjects. For example, neutralizing monoclonal antibodies or HIVIG which prevent the replication of HIV in either mouse or chimpanzee models have been shown to be effective only when the immunotherapeutic is administered immediately prior to viral infection. Treatment with IVIG or HIVIG prior to infection gives the circulating antibodies the opportunity to neutralize the virus as it enters the bloodstream. However, this immunotherapeutic is not effective in pre-existing disease because the immunotherapeutic does not gain access to the intracellular space where the virus replicates.
Another approach has involved the development of a variety of vaccines which have been proposed for use in immunizing individuals against the AIDS virus either before or during the early stages of infection. One such proposed vaccine is an AIDS viral decoy which is described in U.S. Pat. No. 5,334,394. The viral decoy is composed of nanocrystalline particles which mimic the viral core of the AIDS virus. The inert cores are coated with antigenic AIDS viral fragments to produce a non-infective agent which shows promise as an effective immunization agent.
Still other approaches have involved treatments using a wide variety of pharmaceutical agents, such as azidothymidine (AZT), 2',3'-dideoxyinosine (ddI) and 2',3'-dideoxycytidine (ddC). These nucleoside analogs inhibit reverse transcriptase, the enzyme which converts viral RNA to proviral DNA, but do not prevent expression of viral genome and onset of the latent disease. AZT has been shown to prolong the life of AIDS patients for at least one year. However, use of these drugs is limited due to serious toxic side effects including immunosuppression.
Another class of anti-AIDS drugs are protease inhibitors. These drugs prevent the replication of AIDS virus by interfering with the production of proteins vital for the assembly of virus particles. Individually, these products have not been effective due to emergence of resistance to these treatments. A combination of these treatments has been proposed to increase efficacy of these drugs.
Purified IL-2 which stimulates the production of CD4 cells has been reported to improve CD4 count of AIDS patients. The drug is very expensive and causes serious side effects which have symptoms similar to acute influenza. The toxicity of IL-2 may be due to an excess of the growth factor in the cellular system which could overwhelm the feedback control systems, which maintain the integrity and control of the host immune response.
The wide variety of AIDS treatment protocols which are presently available provide an equally wide array of treatment efficacies. To date, none of the procedures have been found to be entirely satisfactory when taken alone or in combination. Accordingly, there is a continuing and pressing need to develop new pharmaceutical preparations and treatment protocols which are useful in treating individuals infected with the AIDS virus.
Plants have proved to be a rich source of drugs for modern medicine. There are hundreds of plants and herbs which have been used for the treatment of different diseases all over the world. Most of these treatments are non-toxic and non-immunosuppressive. There are quite a number of modem chemotherapeutic drugs, like Vinca alkaloids, adriamycin and taxol, which have been isolated from natural sources and are currently used to treat different malignancies. The major disadvantage in use of purified single components is emergence of drug resistance and serious toxic side effects at therapeutic doses. Combination therapies, as evidenced by herbal products, reduce the emergence of drug resistances.
Mistletoe plants belong to the genus Viscum (family, Loranthaceae), which contains a variety of semiparasitic plants found all over the world. The European variety of mistletoe is called Viscum album lanatum which grows on deciduous trees like apple, oak, pine, and sycamore. The plant in ancient Europe was held in great reverence and respected by Druids, as it was used by pagan priests to effect "wonderful" cures. This may be the reason that it has been incorporated as a part of home decoration at Christmas. The medicinal properties of mistletoe include many domestic remedies, e.g., as a tonic in nervous disorders, for treatment of convulsions, delirium, and epilepsy.
Aqueous extracts of mistletoe have been made commercially available in Europe under the tradenames "Iscador," "Helixor" and "Plenosal." The better known "Iscador" is available in the form of different preparations for the treatment of postoperative human neoplasm, and there are several reports of its beneficial effects for breast, lung, and colon carcinoma. However, due to the lack of carefully controlled clinical studies, the merits of Iscador use for cancer treatment have been controversial. The major problems involved in the use of mistletoe preparations, like most herbal products, have been the lack of methods for the manufacture of a standard preparation and uniform quality control. These preparations, especially Iscador, unlike conventional cancer treatments, are nontoxic and effectively induce a beneficial immune stimulatory response in cancer patients.